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Title: Varying Chirality Across Nicotinic Acetylcholine Receptor Subtypes: Selective Binding of Quinuclidine Triazole Compounds
Authors: Jiradanai Sarasamkan
Matthias Scheunemann
Nattayaporn Apaijai
Siripong Palee
Warisara Parichatikanond
Kuntarat Arunrungvichian
Steffen Fischer
Siriporn Chattipakorn
Winnie Deuther-Conrad
Gerrit Schüürmann
Peter Brust
Opa Vajragupta
Mahidol University
Helmholtz-Zentrum Dresden-Rossendorf
Chulabhorn Hospital
Chiang Mai University
Helmholtz Zentrum für Umweltforschung
Technische Universitat Bergakademie Freiberg
Keywords: Biochemistry, Genetics and Molecular Biology;Chemistry
Issue Date: 13-Oct-2016
Citation: ACS Medicinal Chemistry Letters. Vol.7, No.10 (2016), 890-895
Abstract: © 2016 American Chemical Society. The novel quinuclidine anti-1,2,3-triazole derivatives T1-T6 were designed based on the structure of QND8. The binding studies revealed that the stereochemistry at the C3 position of the quinuclidine scaffold plays an important role in the nAChR subtype selectivity. Whereas the (R)-enantiomers are selective to α7 over α4β2 (by factors of 44-225) and to a smaller degree over α3β4 (3-33), their (S)-counterparts prefer α3β4 over α4β2 (62-237) as well as over α7 (5-294). The (R)-derivatives were highly selective to α7 over α3β4 subtypes compared to (RS)- and (R)-QND8. The (S)-enantiomers are 5-10 times more selective to α4β2 than their (R) forms. The overall strongest affinity is observed for the (S)-enantiomer binding to α3β4 (Ki, 2.25-19.5 nM) followed by their (R)-counterpart binding to α7 (Ki, 22.5-117 nM), with a significantly weaker (S)-enantiomer binding to α4β2 (Ki, 414-1980 nM) still above the very weak respective (R)-analogue affinity (Ki, 5059-10436 nM).
ISSN: 19485875
Appears in Collections:Scopus 2016-2017

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